The Pépin Laboratory

The Pépin Laboratory in the Department of Surgery at Massachusetts General Hospital is exploring the basic biology of how hormones regulate female reproductive development with the goal of translating curiosity-driven research to the clinic to benefit Women’s health. In addition to sex steroids, the ovary produces a number of other less understood reproductive hormones such as the anti-Müllerian hormone (AMH, also known as Mullerian inhibiting substance, or MIS) and follistatin (FST), which are necessary for female health. While we continue to apply novel technologies to pursue all aspects of reproduction, contraception, oncofertility, reproductive aging, and oncology, our ultimate goal is to develop therapeutics capable of modulating the MIS and FST pathways and evaluate them in our fertility and ovarian cancer models to develop new treatments that address unmet clinical needs in women’s health and beyond.

Our Mission

Explore curiosity driven research in reproductive development, learn how eggs stay dormant, learn how the female reproductive tract is made, and learn how it goes wrong in cancer. Follow the science first, but keep the patients in our minds: treat infertility, develop new therapies for ovarian cancer, provide more contraceptive choices, improve Women’s health. And have fun doing it!

The Research

Contraception

Our goal is to develop a new class of hormonal contraceptives that act on primordial follicle activation, the initial step of ovarian follicular development. We have identified anti-Müllerian hormone (AMH) as an inhibitory hormone that can induce long-term contraception in mammals, and its receptor AMHR2 as a promising druggable therapeutic target for contraception (Kano et al., 2017).

These discoveries culminated with the development of gene therapy technologies to deliver a safe and effective alternative to surgical sterilization in female cats (Vandsandt et al., 2023) and dogs thanks to the support of the Michelson Found Animals Foundation. We hope our work in the development of contraceptive for use in companion animals will contribute to promote animal welfare and reduce feral animal overpopulation.

In humans, contraceptives that inhibit early follicle development rather than ovulation, as current oral contraceptives do, could have many unexplored advantages, such as fewer side effects, lack of menses, and potentially delayed ovarian aging. Based on these properties we have active projects to develop novel contraceptive molecules targeting AMHR2 which we hope could empower women’s reproductive choices in the developing world, thanks to the support of the Bill and Melinda Gates Foundation.

Female domestic cats involved in the study of the viral-vectored delivery of a feline AMH transgene as a contraceptive strategy.

Oocyte counting by organ clarification to evaluate the ovarian-suppressive effect of MIS.

Oocyte counting by organ clarification to evaluate the ovarian-suppressive effect of AMH.

Expression of MISR2 (green) in granulosa cells of all follicle types.

Expression of murine AMHR2 (green) in granulosa cells of all follicle types.

Oncofertility and aging

Women are born with a set number of eggs, representing their “ovarian reserve” which is used throughout their life and depleted at menopause. As the ovarian reserve declines, either because of toxic chemotherapy, genetic predispositions, or natural aging, the hormones produced by the ovary decrease, which negatively affects many aspects of health including bone loss, cardiovascular diseases, reproductive disorders, and problems with sleep amongst others. Developing methods to slow down the depletion of ovarian reserve could be highly beneficial for women’s health. Maintenance of ovarian reserve as we have demonstrated with AMH treatment in mouse models of chemotherapy (Kano et al., 2017), could have broad applications in the clinic, from preserving fertility and hormonal health in aging women to delaying ovarian insufficiency in genetically susceptible women or patients undergoing chemotherapy. Our laboratory aims to understand how chemotherapy damages the ovary and uterus, and how we may help preserve fertility and hormonal health in women cancer survivors in an NICHD sponsored study.

Reproductive development and infertility

Controlling early follicle development with AMH also has unexpected applications in the treatment of infertility. We have found that pre-treatment with AMH can help recruit a large wave of synchronized follicles and increase the success of ovarian stimulation for IVF (Kano et al., 2019). The laboratory is exploring the role of AMH in all aspects of follicular development with the goal of improving the care of Reproductive Endocrinology and Infertility patients.

Furthermore, uterine-factor infertility has long been a black box in reproduction. While we have a good understanding of factors affecting ovulation and gamete health, the uterine causes of implantation failure, fetal loss, and pre-term labor remain poorly understood. We have identified a novel progenitor cell in the developing uterus, present in mice, rats, and humans, which when dysregulated can lead to severe uterine hypoplasia and infertility later in life (Saatcioglu et al., 2019). Understanding how the uterus develops may be key to explain different disorders of Müllerian development, ranging from Müllerian agenesis to uterine malformations, and uterine hypoplasia.  

uterusctl.jpg
Uterine hypoplasia (bottom) following chemotherapy compared to control (above).

Uterine hypoplasia (right) following chemotherapy compared to control (left).

Ovarian cancer

Ovarian cancer is an insidious disease with 70% recurrence, an almost universal death knell even after effective debulking intraperitoneal surgery and apparent complete response to chemotherapy. Approximately 15,000 women die from ovarian cancer every year in the US. The focus of the laboratory for the past few years has been to apply new emerging technologies to the treatment of this disease, from gene therapy delivery of inhibitory hormones (Pepin et al 2015), to in vivo CRISPR-Cas9 gene editing of patient-specific cancer susceptibilities, and the development of novel immunotherapies thanks to studies sponsored by the Department of Defense, the Ovarian Cancer Research Alliance, and the Koch Institute.

Using novel mouse models of ovarian cancer developed in collaboration with Robert Weinberg at the Whitehead Institute, we have identified mechanisms of resistance to currently available immunotherapies, which have had limited success in ovarian cancer. In particular, we have recently identified follistatin (FST) as a novel immunotherapy target which when inhibited can solicit complete responses to immune checkpoint therapy in ovarian cancer (Iyer et al., 2020).

The publication of new syngeneic mouse models of ovarian cancer and the identification of Fst as a new immune checkpoint resistance target.

The publication of new syngeneic mouse models of ovarian cancer and the identification of FST as a new immune checkpoint resistance target.

Recent Papers

  1. Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries. Meinsohn MC, Saatcioglu HD, Wei L, Li Y, Horn H, Chauvin M, Kano M, Nguyen NMP, Nagykery N, Kashiwagi A, Samore WR, Wang D, Oliva E, Gao G, Morris ME, Donahoe PK, Pépin D. Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2100920118. doi: 10.1073/pnas.2100920118. PMID: 33980714.

  2. Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation. Matute J, Finander B, Pepin D, Ai X, Smith N, Li J, Edlow A, Villani A, Lerou P, Kalish B. Res Sq. 2021 Mar 16:rs.3.rs-311000. doi: 10.21203/rs.3.rs-311000/v1. Preprint. PMID: 33758834 Free PMC article.

  3. Blocking estrogen-induced AMH expression is crucial for normal follicle formation. Tanimoto R, Sekii K, Morohaku K, Li J, Pépin D, Obata Y. Development. 2021 Mar 19;148(6):dev197459. doi: 10.1242/dev.197459. PMID: 33658225

  4. Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells. Chauvin M, Garambois V, Colombo PE, Chentouf M, Gros L, Brouillet JP, Robert B, Jarlier M, Dumas K, Martineau P, Navarro-Teulon I, Pépin D, Chardès T, Pèlegrin A. Sci Rep. 2021 Jan 26;11(1):2231. doi: 10.1038/s41598-021-81819-y. PMID: 33500516 Free PMC article.

  5. Compromised SARS-CoV-2-specific placental antibody transfer. Atyeo C, Pullen KM, Bordt EA, Fischinger S, Burke J, Michell A, Slein MD, Loos C, Shook LL, Boatin AA, Yockey LJ, Pepin D, Meinsohn MC, Nguyen NMP, Chauvin M, Roberts D, Goldfarb IT, Matute JD, James KE, Yonker LM, Bebell LM, Kaimal AJ, Gray KJ, Lauffenburger D, Edlow AG, Alter G. Cell. 2021 Feb 4;184(3):628-642.e10. doi: 10.1016/j.cell.2020.12.027. Epub 2020 Dec 23. PMID: 33476549 Free PMC article.

  6. A genome-wide strategy to identify causes and consequences of retrotransposon expression finds activation by BRCA1 in ovarian cancer. Alkailani M, Palidwor G, Poulin A, Mohan R, Pepin D, Vanderhyden B, Gibbings D. NAR Cancer. 2021 Mar;3(1):zcaa040. doi: 10.1093/narcan/zcaa040. Epub 2021 Jan 6. PMID: 33447827 Free PMC article.

  7. A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation. Meinsohn MC, Hughes CHK, Estienne A, Saatcioglu HD, Pépin D, Duggavathi R, Murphy BD. Sci Rep. 2021 Jan 13;11(1):1079. doi: 10.1038/s41598-020-80178-4. PMID: 33441767 Free PMC article.

  8. Assessment of Maternal and Neonatal SARS-CoV-2 Viral Load, Transplacental Antibody Transfer, and Placental Pathology in Pregnancies During the COVID-19 Pandemic. Edlow AG, Li JZ, Collier AY, Atyeo C, James KE, Boatin AA, Gray KJ, Bordt EA, Shook LL, Yonker LM, Fasano A, Diouf K, Croul N, Devane S, Yockey LJ, Lima R, Shui J, Matute JD, Lerou PH, Akinwunmi BO, Schmidt A, Feldman J, Hauser BM, Caradonna TM, De la Flor D, D'Avino P, Regan J, Corry H, Coxen K, Fajnzylber J, Pepin D, Seaman MS, Barouch DH, Walker BD, Yu XG, Kaimal AJ, Roberts DJ, Alter G. JAMA Netw Open. 2020 Dec 1;3(12):e2030455. doi: 10.1001/jamanetworkopen.2020.30455. PMID: 33351086 Free PMC article.

  9. Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy. Iyer S, Zhang S, Yucel S, Horn H, Smith SG, Reinhardt F, Hoefsmit E, Assatova B, Casado J, Meinsohn MC, Barrasa MI, Bell GW, Pérez-Villatoro F, Huhtinen K, Hynninen J, Oikkonen J, Galhenage PM, Pathania S, Hammond PT, Neel BG, Farkkila A, Pépin D, Weinberg RA. Cancer Discov. 2021 Feb;11(2):384-407. doi: 10.1158/2159-8290.CD-20-0818. Epub 2020 Nov 6. PMID: 33158843

  10. Follicular fluid anti-Müllerian hormone (AMH) concentrations and outcomes of in vitro fertilization cycles with fresh embryo transfer among women at a fertility center. Sacha CR, Chavarro JE, Williams PL, Ford J, Zhang L, Donahoe PK, Souter IC, Hauser R, Pépin D, Mínguez-Alarcón L; EARTH Study Team. J Assist Reprod Genet. 2020 Nov;37(11):2757-2766. doi: 10.1007/s10815-020-01956-7. Epub 2020 Oct 6. PMID: 33025399

  11. Mutational Analysis of the Putative Anti-Müllerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2. Hart KN, Pépin D, Czepnik M, Donahoe PK, Thompson TB. Endocrinology. 2020 Jul 1;161(7):bqaa066. doi: 10.1210/endocr/bqaa066. PMID: 32333774 Free PMC article.

  12. Neoadjuvant Treatment With Müllerian-Inhibiting Substance Synchronizes Follicles and Enhances Superovulation Yield. Kano M, Hsu JY, Saatcioglu HD, Nagykery N, Zhang L, Morris Sabatini ME, Donahoe PK, Pépin D. J Endocr Soc. 2019 Jul 22;3(11):2123-2134. doi: 10.1210/js.2019-00190. eCollection 2019 Nov 1. PMID: 31687639 Free PMC article.

  13. Single-cell sequencing of neonatal uterus reveals an Misr2+ endometrial progenitor indispensable for fertility. Saatcioglu HD, Kano M, Horn H, Zhang L, Samore W, Nagykery N, Meinsohn MC, Hyun M, Suliman R, Poulo J, Hsu J, Sacha C, Wang D, Gao G, Lage K, Oliva E, Morris Sabatini ME, Donahoe PK, Pépin D. Elife. 2019 Jun 24;8:e46349. doi: 10.7554/eLife.46349. PMID: 31232694 Free PMC article.

  14. Müllerian inhibiting substance/anti-Müllerian hormone as a fertility preservation agent. Pépin D, Sabatini ME, Donahoe PK. Curr Opin Endocrinol Diabetes Obes. 2018 Dec;25(6):399-405. doi: 10.1097/MED.0000000000000442. PMID: 30320617 Review.

  15. Towards international standardization of immunoassays for Müllerian inhibiting substance/anti-Müllerian hormone. Ferguson JM, Pépin D, Duru C, Matejtschuk P, Donahoe PK, Burns CJ. Reprod Biomed Online. 2018 Nov;37(5):631-640. doi: 10.1016/j.rbmo.2018.08.012. Epub 2018 Sep 5. PMID: 30241771 Free PMC article.

  16. Müllerian-Inhibiting Substance/Anti-Müllerian Hormone as a Predictor of Preterm Birth in Polycystic Ovary Syndrome. Hsu JY, James KE, Bormann CL, Donahoe PK, Pépin D, Sabatini ME. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4187-4196. doi: 10.1210/jc.2018-01320. PMID: 30239805

  17. Quantification of Müllerian Inhibiting Substance/Anti-Müllerian Hormone polypeptide by isotope dilution mass spectrometry. Whiting G, Ferguson J, Fang M, Pepin D, Donahoe P, Matejtschuk P, Burns C, Wheeler JX. Anal Biochem. 2018 Nov 1;560:50-55. doi: 10.1016/j.ab.2018.05.006. Epub 2018 May 6. PMID: 29742446

  18. Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer. Qi R, Wang Y, Bruno PM, Xiao H, Yu Y, Li T, Lauffer S, Wei W, Chen Q, Kang X, Song H, Yang X, Huang X, Detappe A, Matulonis U, Pepin D, Hemann MT, Birrer MJ, Ghoroghchian PP. Nat Commun. 2017 Dec 18;8(1):2166. doi: 10.1038/s41467-017-02390-7. PMID: 29255160 Free PMC article.

  19. Müllerian inhibiting substance inhibits an ovarian cancer cell line via β-catenin interacting protein deregulation of the Wnt signal pathway. Park SH, Chung YJ, Song JY, Kim SI, Pépin D, MacLaughlin DT, Donahoe PK, Kim JH. Int J Oncol. 2017 Mar;50(3):1022-1028. doi: 10.3892/ijo.2017.3874. Epub 2017 Feb 13. PMID: 28197641

  20. AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. Kano M, Sosulski AE, Zhang L, Saatcioglu HD, Wang D, Nagykery N, Sabatini ME, Gao G, Donahoe PK, Pépin D. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1688-E1697. doi: 10.1073/pnas.1620729114. Epub 2017 Jan 30. PMID: 28137855 Free PMC article.

  21. Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer. Beck TN, Korobeynikov VA, Kudinov AE, Georgopoulos R, Solanki NR, Andrews-Hoke M, Kistner TM, Pépin D, Donahoe PK, Nicolas E, Einarson MB, Zhou Y, Boumber Y, Proia DA, Serebriiskii IG, Golemis EA. Cell Rep. 2016 Jul 19;16(3):657-71. doi: 10.1016/j.celrep.2016.06.043. Epub 2016 Jul 7. PMID: 27396341 Free PMC article.

  22. CD44 Splice Variant v8-10 as a Marker of Serous Ovarian Cancer Prognosis. Sosulski A, Horn H, Zhang L, Coletti C, Vathipadiekal V, Castro CM, Birrer MJ, Nagano O, Saya H, Lage K, Donahoe PK, Pépin D. PLoS One. 2016 Jun 2;11(6):e0156595. doi: 10.1371/journal.pone.0156595. eCollection 2016. PMID: 27253518 Free PMC article.

  23. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer. Pépin D, Sosulski A, Zhang L, Wang D, Vathipadiekal V, Hendren K, Coletti CM, Yu A, Castro CM, Birrer MJ, Gao G, Donahoe PK. Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4418-27. doi: 10.1073/pnas.1510604112. Epub 2015 Jul 27. PMID: 26216943 Free PMC article.

  24. Effect of p53 activity on the sensitivity of human glioblastoma cells to PARP-1 inhibitor in combination with topoisomerase I inhibitor or radiation. Sabbatino F, Fusciello C, Somma D, Pacelli R, Poudel R, Pepin D, Leonardi A, Carlomagno C, Della Vittoria Scarpati G, Ferrone S, Pepe S. Cytometry A. 2014 Nov;85(11):953-61. doi: 10.1002/cyto.a.22563. Epub 2014 Sep 2. PMID: 25182801

  25. PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Sabbatino F, Wang Y, Wang X, Flaherty KT, Yu L, Pepin D, Scognamiglio G, Pepe S, Kirkwood JM, Cooper ZA, Frederick DT, Wargo JA, Ferrone S, Ferrone CR. Oncotarget. 2014 Apr 15;5(7):1926-41. doi: 10.18632/oncotarget.1878. PMID: 24732172 Free PMC article.

  26. The imitation switch ATPase Snf2l is required for superovulation and regulates Fgl2 in differentiating mouse granulosa cells. Pépin D, Paradis F, Perez-Iratxeta C, Picketts DJ, Vanderhyden BC. Biol Reprod. 2013 Jun 6;88(6):142. doi: 10.1095/biolreprod.112.105742. Print 2013 Jun. PMID: 23616592

  27. Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Meirelles K, Benedict LA, Dombkowski D, Pepin D, Preffer FI, Teixeira J, Tanwar PS, Young RH, MacLaughlin DT, Donahoe PK, Wei X. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2358-63. doi: 10.1073/pnas.1120733109. Epub 2012 Jan 27. PMID: 22308459 Free PMC article.

  28. Kallikreins 5, 6 and 10 differentially alter pathophysiology and overall survival in an ovarian cancer xenograft model. Pépin D, Shao ZQ, Huppé G, Wakefield A, Chu CW, Sharif Z, Vanderhyden BC. PLoS One. 2011;6(11):e26075. doi: 10.1371/journal.pone.0026075. Epub 2011 Nov 15. PMID: 22102857 Free PMC article.

  29. ISWI chromatin remodeling in ovarian somatic and germ cells: revenge of the NURFs. Pépin D, Vanderhyden BC, Picketts DJ, Murphy BD. Trends Endocrinol Metab. 2007 Jul;18(5):215-24. doi: 10.1016/j.tem.2007.05.004. Epub 2007 Jun 1. PMID: 17544291 Review.

  30. The imitation switch protein SNF2L regulates steroidogenic acute regulatory protein expression during terminal differentiation of ovarian granulosa cells. Lazzaro MA, Pépin D, Pescador N, Murphy BD, Vanderhyden BC, Picketts DJ. Mol Endocrinol. 2006 Oct;20(10):2406-17. doi: 10.1210/me.2005-0213. Epub 2006 Jun 1. PMID: 16740656